Meeting News

Enrollment on genomically matched clinical trials improves sarcoma outcomes

 
Vivek Subbiah
Shiraj Sen, MD, PhD 
Shiraj Sen

CHICAGO — Patients with various subtypes of pretreated, metastatic sarcoma showed improved response rates and survival when treated on genomically matched phase 1 trials, according to study results presented at ASCO Annual Meeting.

“Sarcoma is not one disease; sarcoma is hundreds of diseases,” Vivek Subbiah, MD, associate professor in the department of investigational cancer therapeutics and medical director of the Center for Targeted Therapy at The University of MD Anderson Cancer Center, told HemOnc Today. “Sarcoma represents a heterogenetic group of rare malignancies that encompass less than 1% of adult and 12% of pediatric cancers. WHO has identified more than 50 sarcoma subtypes, but we actually have at least 100 subtypes when we slice and dice the sarcoma.”

The challenge has been in the one-size-fits-all nature of sarcoma trials, which consider patients with sarcoma as a whole, Subbiah added. Early trials may show some efficacy, but the responses don’t persist in later trials after randomization, as was exemplified with the negative phase 3 ANNOUNCE trial of olaratumab (Lartruvo, Eli Lilly) presented during ASCO’s plenary session.

“Drug development in sarcomas remains challenging, with few effective FDA approved therapies,” study author Shiraj Sen, MD, PhD, associate director of the drug development unit at Sarah Cannon Research Institute, told HemOnc Today. “Fortunately, recent genomic analyses have revealed many potentially actionable mutations across sarcoma subtypes. However, the actionability of these potential driver mutations remains unclear and whether patients enrolled on genomically matched early-phase trials have improved outcomes over patients enrolled on non-genomically matched trials remains unknown.”

Subbiah, Sen and colleagues analyzed clinical and next-generation sequencing data from 406 patients (median age, 53 years; range, 11-84; 48% female) with sarcoma — including 321 with soft tissue sarcomas and 85 with bone sarcomas — treated on phase 1 clinical trials between May 2006 and May 2018 at MD Anderson Cancer Center. Patients had received a median of three (range, 0-9) prior lines of therapy.

“Our main goals were to determine whether next-generation sequencing has affected drug development in sarcoma, and how to optimize precision medicine for sarcoma,” Subbiah said.

The most common soft tissue sarcoma subtypes included leiomyosarcoma (16%), liposarcoma (13%), gastrointestinal stromal tumors (11%) and synovial sarcoma (3%). The most common bone sarcomas in the population included osteosarcoma (8%), chondrosarcoma (7%) and Ewing sarcoma (6%).

Of these patients, 250 underwent next-generation sequencing and 156 did not. Twenty-three percent of the patients (n = 93) received treatment on genomically matched trials. The 313 patients enrolled onto nongenomically matched trials received treatments such as immunotherapy, monoclonal antibodies and antibody-drug conjugates, Subbiah said.

“We saw that next-generation sequencing was not commonly practiced among patients with sarcoma, and clinical selection for patients with metastatic, refractory sarcoma remains challenging,” he said. “The low number of patients undergoing sequencing was surprising, but we don’t have that many targeted therapies for sarcoma as standard of care. We will probably see more patients being sequenced over the next few years.”

Researchers found that patients treated on genomically matched trials had a higher rate of response to treatment, at 11%, compared with 6% among those who were not treated on such a trial (OR = 1.97; 95% CI, 0.88-4.44). Responses occurred for patients receiving novel agents that targeted TRK, LRRC15, cMET, mTOR, VEGF, MDM2, KIT/PDGFRA and FGFR.

“Eleven percent is low, but these are patients who progressed on several standard lines of therapy,” Subbiah said. “We need to take all of these data with a grain of salt because they are retrospective data, but this can provide a threshold for prospective biomarker development in genomically matched basket studies in sarcoma.”

Patients treated on genomically matched trials had a significantly longer median time to progression — albeit only by 1 month (3.7 months vs. 2.7 months; HR = 0.72; 95% CI, 0.57-0.91) — and a significantly higher clinical benefit rate (41% vs. 19%; OR = 2.91; 95% CI, 1.77-4.8).

Median OS was 22.1 months for patients genomically matched to treatment vs. 15.5 months for the other patients (HR = 0.7; 95% CI, 0.5-0.98), which represented a significant improvement.

“There was no statistically significant difference in response rate between the two groups, but enrollment onto genomically matched early-phase trials was associated with an improvement in clinical benefit rate, median time to progression and median OS,” Sen told HemOnc Today. “More research is needed to determine which patients will derive the most clinically meaningful benefit from genomically matched treatments. In this study, we identify some of these genomic alterations where responses were seen in heavily pre-treated, refractory sarcomas — KIT/PDGFR, MDM2, cMET, TRK and FGFR.”

Moving forward, sarcoma trials should be designed using the basket or umbrella concepts, Subbiah said. The basket concept involves sequencing patients and matching them to several targeted therapies based on their molecular profile, whereas the umbrella concept involves developing clinical studies for each sarcoma subtype.

“We need to develop studies for each of these sarcoma subtypes, even if it enrolls 10 to 20 patients, because they are different diseases,” Subbiah said. “The future paradigm should be that even if it is a handful of patients, we need to offer precision therapy for every type of sarcoma.”

Subbiah said some may ask whether this is feasible, but his answer is yes.

“With high response rates, drugs can be approved even with less than 30 patients in an arm,” he said. “There are drugs approved for rare cancers, like anaplastic thyroid cancer, for which the FDA last year approved dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) based on less than 20 patients with response. The key is moving on from one size fits all to slicing and dicing sarcoma.” – by Alexandra Todak

Reference:

Sen S, et al. Abstract 11018. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Sen reports a consultant/advisory role with Daiichi Sankyo and research funding to his institution from BioAlta, Exelixis, Jacobio and Loxo Oncology. Subbiah reports a consultant/advisory role with MedImmune; research funding to his institution from AbbVie, Agensys, Alfasigma, Amgen, Bayer, Berg Pharma, Blueprint Medicines, Boston Biomedical, D3 Oncology Solutions, Exelixis, Fujifilm, Genentech/Roche, GlaxoSmithKline, Idera, Incyte, Inhibrx, Loxo Oncology, Multivir, NanoCarrier, Northwest Biotherapeutics, Novartis, Pfizer, PharmaMara, Takeda and Vegenics; and travel expenses from Bayer and PharmaMar. Please see the abstract for all other authors’ relevant financial disclosures.

 
Vivek Subbiah
Shiraj Sen, MD, PhD 
Shiraj Sen

CHICAGO — Patients with various subtypes of pretreated, metastatic sarcoma showed improved response rates and survival when treated on genomically matched phase 1 trials, according to study results presented at ASCO Annual Meeting.

“Sarcoma is not one disease; sarcoma is hundreds of diseases,” Vivek Subbiah, MD, associate professor in the department of investigational cancer therapeutics and medical director of the Center for Targeted Therapy at The University of MD Anderson Cancer Center, told HemOnc Today. “Sarcoma represents a heterogenetic group of rare malignancies that encompass less than 1% of adult and 12% of pediatric cancers. WHO has identified more than 50 sarcoma subtypes, but we actually have at least 100 subtypes when we slice and dice the sarcoma.”

The challenge has been in the one-size-fits-all nature of sarcoma trials, which consider patients with sarcoma as a whole, Subbiah added. Early trials may show some efficacy, but the responses don’t persist in later trials after randomization, as was exemplified with the negative phase 3 ANNOUNCE trial of olaratumab (Lartruvo, Eli Lilly) presented during ASCO’s plenary session.

“Drug development in sarcomas remains challenging, with few effective FDA approved therapies,” study author Shiraj Sen, MD, PhD, associate director of the drug development unit at Sarah Cannon Research Institute, told HemOnc Today. “Fortunately, recent genomic analyses have revealed many potentially actionable mutations across sarcoma subtypes. However, the actionability of these potential driver mutations remains unclear and whether patients enrolled on genomically matched early-phase trials have improved outcomes over patients enrolled on non-genomically matched trials remains unknown.”

Subbiah, Sen and colleagues analyzed clinical and next-generation sequencing data from 406 patients (median age, 53 years; range, 11-84; 48% female) with sarcoma — including 321 with soft tissue sarcomas and 85 with bone sarcomas — treated on phase 1 clinical trials between May 2006 and May 2018 at MD Anderson Cancer Center. Patients had received a median of three (range, 0-9) prior lines of therapy.

“Our main goals were to determine whether next-generation sequencing has affected drug development in sarcoma, and how to optimize precision medicine for sarcoma,” Subbiah said.

The most common soft tissue sarcoma subtypes included leiomyosarcoma (16%), liposarcoma (13%), gastrointestinal stromal tumors (11%) and synovial sarcoma (3%). The most common bone sarcomas in the population included osteosarcoma (8%), chondrosarcoma (7%) and Ewing sarcoma (6%).

Of these patients, 250 underwent next-generation sequencing and 156 did not. Twenty-three percent of the patients (n = 93) received treatment on genomically matched trials. The 313 patients enrolled onto nongenomically matched trials received treatments such as immunotherapy, monoclonal antibodies and antibody-drug conjugates, Subbiah said.

“We saw that next-generation sequencing was not commonly practiced among patients with sarcoma, and clinical selection for patients with metastatic, refractory sarcoma remains challenging,” he said. “The low number of patients undergoing sequencing was surprising, but we don’t have that many targeted therapies for sarcoma as standard of care. We will probably see more patients being sequenced over the next few years.”

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Researchers found that patients treated on genomically matched trials had a higher rate of response to treatment, at 11%, compared with 6% among those who were not treated on such a trial (OR = 1.97; 95% CI, 0.88-4.44). Responses occurred for patients receiving novel agents that targeted TRK, LRRC15, cMET, mTOR, VEGF, MDM2, KIT/PDGFRA and FGFR.

“Eleven percent is low, but these are patients who progressed on several standard lines of therapy,” Subbiah said. “We need to take all of these data with a grain of salt because they are retrospective data, but this can provide a threshold for prospective biomarker development in genomically matched basket studies in sarcoma.”

Patients treated on genomically matched trials had a significantly longer median time to progression — albeit only by 1 month (3.7 months vs. 2.7 months; HR = 0.72; 95% CI, 0.57-0.91) — and a significantly higher clinical benefit rate (41% vs. 19%; OR = 2.91; 95% CI, 1.77-4.8).

Median OS was 22.1 months for patients genomically matched to treatment vs. 15.5 months for the other patients (HR = 0.7; 95% CI, 0.5-0.98), which represented a significant improvement.

“There was no statistically significant difference in response rate between the two groups, but enrollment onto genomically matched early-phase trials was associated with an improvement in clinical benefit rate, median time to progression and median OS,” Sen told HemOnc Today. “More research is needed to determine which patients will derive the most clinically meaningful benefit from genomically matched treatments. In this study, we identify some of these genomic alterations where responses were seen in heavily pre-treated, refractory sarcomas — KIT/PDGFR, MDM2, cMET, TRK and FGFR.”

Moving forward, sarcoma trials should be designed using the basket or umbrella concepts, Subbiah said. The basket concept involves sequencing patients and matching them to several targeted therapies based on their molecular profile, whereas the umbrella concept involves developing clinical studies for each sarcoma subtype.

“We need to develop studies for each of these sarcoma subtypes, even if it enrolls 10 to 20 patients, because they are different diseases,” Subbiah said. “The future paradigm should be that even if it is a handful of patients, we need to offer precision therapy for every type of sarcoma.”

Subbiah said some may ask whether this is feasible, but his answer is yes.

“With high response rates, drugs can be approved even with less than 30 patients in an arm,” he said. “There are drugs approved for rare cancers, like anaplastic thyroid cancer, for which the FDA last year approved dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) based on less than 20 patients with response. The key is moving on from one size fits all to slicing and dicing sarcoma.” – by Alexandra Todak

Reference:

Sen S, et al. Abstract 11018. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Sen reports a consultant/advisory role with Daiichi Sankyo and research funding to his institution from BioAlta, Exelixis, Jacobio and Loxo Oncology. Subbiah reports a consultant/advisory role with MedImmune; research funding to his institution from AbbVie, Agensys, Alfasigma, Amgen, Bayer, Berg Pharma, Blueprint Medicines, Boston Biomedical, D3 Oncology Solutions, Exelixis, Fujifilm, Genentech/Roche, GlaxoSmithKline, Idera, Incyte, Inhibrx, Loxo Oncology, Multivir, NanoCarrier, Northwest Biotherapeutics, Novartis, Pfizer, PharmaMara, Takeda and Vegenics; and travel expenses from Bayer and PharmaMar. Please see the abstract for all other authors’ relevant financial disclosures.

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